tbuckley/cabot-search huggingface dataset:
Clinical audit of breast cancer patients under 40 years of age: A single institution experience.
Authors: Shruti Kate, Roshan Patil, Rajnish Vasant Nagarkar, Makarand Arun Randive, Shaunak Valame, Yasam Venkata Ramesh
Journal: Journal of Clinical Oncology (2022)

e12533 Background: Age is an important risk factor for breast cancer (BC). The younger age (&lt; 40 years) is associated with unfavorable tumor biology. This is a retrospective analysis of young breast patients treated from 2012-2020 at a comprehensive cancer centre. Methods: Data regarding demography, clinical presentation, histopathological features, molecular profiling, treatment details, and outcomes were retrieved from medical records. All time-to event outcomes were analyzed using Kaplan-Meir method. Results: A total of 134 patients (&lt; 40 years) with BC were included. Median age of the study cohort was 37 years (range: 22-40 years) with a female predominance (98.5%). Most of the patients presented with locally advanced BC (51%) followed by early BC (43%) and metastatic BC (6%). The mean tumor size and positivity lymph nodes of our non-metastatic patients were 3.86±1.90 cm and 3.3±3.98, respectively. The molecular classification revealed most of the patients were of Basal-like BC (TNBC, 40%) followed by Luminal A (33%), Luminal B (14%) and Her-2 (13%), respectively. Germline BRCA testing was positive in 22% patients (10/45). At a median follow-up of 51 months, 3 and 5-year Kaplan-Meier estimates of overall survival were 67.2% and 44.7%, respectively. Conclusions: Breast cancer is a heterogeneous disease with varied survival depending on multiple factors. Early diagnosis and timely appropriate management, as per clinical and molecular profile provides acceptable outcome.
NOHA: A sensitive, low-cost, and accessible blood-based biomarker to determine breast cancer estrogen receptor status in low-resource settings.
Authors: Srinidi Mohan, Augustine Musyoka, Divya Guthikonda, Jamie Saunders, Lora Girata, Alex Mremi, Furaha Serventi, Blandina Mbaga, Elizabeth Patrick, Michael A Jones, Ivette F. Emery, Frances L. Lucas, Susan Miesfeldt
Journal: Journal of Clinical Oncology (2022)

580 Background: Significant challenges to breast cancer control in low- and middle-income countries (LMICs) include late-stage disease presentation because of few/no early detection programs, inadequately staffed and equipped pathology laboratories, and constrained treatment options. Estrogen receptor (ER) expression is critical to determining candidacy for cost efficient and accessible hormonal agents in LMICs; however, access to standard immunohistochemistry (IHC)-based ER analysis is grossly limited/nonexistent due to cost and technical requirements. We have identified N w -hydroxy-L-Arginine (NOHA) as a low cost and accessible blood-based biomarker to distinguish estrogen-receptor negative (ER – ) from estrogen-receptor positive (ER + ) breast cancer, differentiate ER – high grade versus low grade tumors, and correlate ER – molecular phenotype with ethnic variation. Our studies with US patients suggest the NOHA threshold of &lt;4nM as a reliable indicator of ER – versus ER + disease (Table 1). Here we examine the clinical utility of NOHA as an alternative to IHC in distinguishing ER – from ER + breast tumors in Tanzanian patients. Methods: Following informed consent, 70 newly diagnosed breast cancer patients were recruited at Kilimanjaro Christian Medical Center (KCMC; Moshi, Tanzania). Prior to any treatment, a needle prick amount of blood was collected from each patient on a Noviplex plasma card (Shimadsu, U.S.) and stored at -80˚C. Plasma cards and unstained tumor pathology slides were shipped at 2-3 months intervals to US labs for NOHA and immunohistochemistry (IHC) ER testing. Statistical difference was set at p&lt;0.01, with NOHA and IHC assay operators blinded to patient clinical status. Results: Our early data show correlation between NOHA levels and ER IHC results, providing a means to distinguish ER – from ER + breast cancer in the low-resource setting. Plasma cards stored at -80˚C for up to 3 months retained NOHA stability in assays involving a proprietary antibody-based ELISA, and by LC-MS. Conclusions: This study suggests the clinical utility of NOHA as a cost-effective, accessible replacement for standard IHC testing in determining ER status among breast cancer patients in LMICs, promising to extend access to cost efficient and available hormonal agents and improving outcomes and quality of life. The present study provides foundational knowledge for broader studies of NOHA utility in global breast cancer control, as well as in ongoing development of NOHA rapid-testing technologies. [Table: see text]
Effect of Molnupiravir on Biomarkers, Respiratory Interventions, and Medical Services in COVID-19
Authors: Matthew G. Johnson, Amy Puenpatom, Pablo Andrés Moncada, Lesley Burgess, Elizabeth R. Duke, Norio Ohmagari, Timo Wolf, Matteo Bassetti, Sanjay Bhagani, Jade Ghosn, Ying Zhang, Hong Wan, Angela Williams-Diaz, Michelle L. Brown, Amanda Paschke, Carisa De Anda
Journal: Annals of Internal Medicine (2022)

In the MOVe-OUT trial, molnupiravir showed a clinically meaningful reduction in the risk for hospitalization or death in adults with mild to moderate COVID-19 and risk factors for progression to severe disease.
Dynamic causal communication channels between neocortical areas
Authors: Mitra Javadzadeh, Sonja B. Hofer
Journal: Neuron (2022)

Processing of sensory information depends on the interactions between hierarchically connected neocortical regions, but it remains unclear how the activity in one area causally influences the activity dynamics in another and how rapidly such interactions change with time. Here, we show that the communication between the primary visual cortex (V1) and high-order visual area LM is context-dependent and surprisingly dynamic over time. By momentarily silencing one area while recording activity in the other, we find that both areas reliably affected changing subpopulations of target neurons within one hundred milliseconds while mice observed a visual stimulus. The influence of LM feedback on V1 responses became even more dynamic when the visual stimuli predicted a reward, causing fast changes in the geometry of V1 population activity and affecting stimulus coding in a context-dependent manner. Therefore, the functional interactions between cortical areas are not static but unfold through rapidly shifting communication subspaces whose dynamics depend on context when processing sensory information.
Silk-based hydrogel incorporated with metal-organic framework nanozymes for enhanced osteochondral regeneration
Authors: Zhicheng Cao, Hongmei Wang, Jialin Chen, Yanan Zhang, Qingyun Mo, Po Zhang, Mingyue Wang, Haoyang Liu, Xueyang Bao, Yuzhi Sun, Wei Zhang, Qingqiang Yao
Journal: Bioactive Materials (2022)

Osteochondral defects (OCD) cannot be efficiently repaired due to the unique physical architecture and the pathological microenvironment including enhanced oxidative stress and inflammation. Conventional strategies, such as the control of implant microstructure or the introduction of growth factors, have limited functions failing to manage these complex environments. Here we developed a multifunctional silk-based hydrogel incorporated with metal-organic framework nanozymes (CuTA@SF) to provide a suitable microenvironment for enhanced OCD regeneration. The incorporation of CuTA nanozymes endowed the SF hydrogel with a uniform microstructure and elevated hydrophilicity. In vitro cultivation of mesenchymal stem cells (MSCs) and chondrocytes showed that CuTA@SF hydrogel accelerated cell proliferation and enhanced cell viability, as well as had antioxidant and antibacterial properties. Under the inflammatory environment with the stimulation of IL-1β, CuTA@SF hydrogel still possessed the potential to promote MSC osteogenesis and deposition of cartilage-specific extracellular matrix (ECM). The proteomics analysis further confirmed that CuTA@SF hydrogel promoted cell proliferation and ECM synthesis. In the full-thickness OCD model of rabbit, CuTA@SF hydrogel displayed successfully in situ OCD regeneration, as evidenced by micro-CT, histology (HE, S/O, and toluidine blue staining) and immunohistochemistry (Col I and aggrecan immunostaining). Therefore, CuTA@SF hydrogel is a promising biomaterial targeted at the regeneration of OCD.
Urban-rural kidney cancer disparities: The role of health literacy, cancer literacy, smoking status, and urinary bother.
Authors: Christina Su, Erin Linnenbringer, Danuta Dynda, Kristin Delfino, Sarah Lyons, Sharon Kim, Shaheen Alanee, Kevin McVary
Journal: Journal of Clinical Oncology (2022)

e16513 Background: Kidney cancer (KCa) does not currently have efficacious screening methods, therefore targeting modifiable risk factors is a strong approach to primary prevention. Prior research from our group identified a significant difference in KCa incidence and mortality between the urban and rural populations in Illinois, but the reason(s) for this geographic variation were unclear. The objective of this pilot study was to investigate KCa-relevant knowledge and health behaviors in order to explain our observed urban-rural differences in KCa incidence and mortality, and to inform approaches to KCa prevention. Methods: A convenience sample was surveyed from five study sites between June 2016 and February 2018. These included 207 urban and 53 rural patients presenting at urology and primary care clinics. Four outcome measures related to KCa were assessed using validated measures: 1) health literacy, 2) cancer health literacy, 3) smoking status and knowledge of its association with KCa, and 4) degree of bother caused by urologic symptoms. Multivariate logistic regression models were used to examine these outcome measures between the two populations. Smoking history, personal and family history of cancer, and socio-demographic characteristics were controlled for in the analysis. Results: The overall model for predicting health literacy was significant (Wald Pvalue = 0.0269). When accounting for all covariates, rural versus urban residence was not a significant predictor of adequate health literacy (p = 0.4871). However, participants with higher levels of education (p = 0.0005), higher household income (p = 0.0395), and participants who were female (p = 0.0104) were all more likely to have adequate vs. low health literacy. We did not identify a statistically significant difference in cancer health literacy, knowledge of smoking as a KCa risk factor, or measurement of urinary bother between urban and rural residents in this population. Conclusions: The analyses revealed significant differences in health literacy by education, income, and gender, but not by geographic location. While there were no statistically significant geographical differences found in three of our four domains, this may have been attributed to the low proportion of rural-residing clinic patients recruited in this study. With potential limitations of using RUCA as a measure of rurality, future work is needed to better reach this population and validate results to understand the disparity of improving KCa outcomes in rural areas.
Two-year update from KEYNOTE-799: Pembrolizumab plus concurrent chemoradiation therapy (cCRT) for unresectable, locally advanced, stage III NSCLC.
Authors: Martin Reck, Ki Hyeong Lee, Nicolaj Frost, Valeriy Vladimirovich Breder, Dariusz Kowalski, Evgeny Levchenko, Noemi Reguart, Alex Martinez-Marti, Baerin Houghton, Jean-Baptiste Paoli, Sufiia Safina, Takefumi Komiya, Amy Sanford, Hong Liu, Andrew J. Song, Steven M. Keller, Salma K. Jabbour
Journal: Journal of Clinical Oncology (2022)

8508 Background: Primary analysis (database cutoff, Oct 28, 2020) of the global KEYNOTE-799 study (NCT03631784) in patients (pts) with unresectable, locally advanced stage III NSCLC, showed that pembrolizumab (pembro; anti–PD-1) plus cCRT resulted in an ORR of 70.5% in cohort A (n = 112; squamous and nonsquamous) and 70.6% in cohort B (n = 102; nonsquamous only) and grade ≥3 pneumonitis in 9 (8.0%) and 7 (6.9%) pts, respectively. We present updated outcomes with 1 y of additional follow-up. Methods: In this nonrandomized, phase 2 study, eligible pts were aged ≥18 y with previously untreated, unresectable, pathologically confirmed, stage IIIA-C NSCLC with measurable disease per RECIST v1.1. Pts in cohort A (squamous and nonsquamous) received carboplatin AUC 6 plus paclitaxel 200 mg/m 2 and pembro 200 mg for one 3-wk cycle, followed by carboplatin AUC 2 plus paclitaxel 45 mg/m 2 QW for 6 wks plus 2 cycles of pembro 200 mg Q3W plus standard thoracic radiotherapy (TRT). Pts in cohort B (nonsquamous) received 3 cycles of cisplatin 75 mg/m 2 , pemetrexed 500 mg/m 2 , and pembro 200 mg Q3W plus standard TRT in cycles 2 and 3. All pts received 14 additional cycles of pembro 200 mg Q3W. Primary endpoints were ORR per RECIST v1.1 by blinded independent central review (BICR) and the incidence of grade ≥3 pneumonitis (per NCI CTCAE v4.0). Results: Of 216 pts enrolled in this study, 112 in cohort A and 102 in cohort B received treatment. Median (range) time from first dose to database cutoff (Oct 18, 2021) was 30.2 (25.3–35.5) mo in cohort A and 25.4 (14.5–35.2) mo in cohort B. ORR (95% CI) was 71.4% (62.1%–79.6%) in cohort A and 75.5% (66.0%–83.5%) in cohort B. Median duration of response (DOR) and OS were not reached (NR) in both cohorts; median PFS was 30.6 mo in cohort A, and NR in cohort B (Table). ORR was 66.7% in pts with PD-L1 TPS &lt;1% and 77.3% in pts with PD-L1 TPS ≥1% in cohort A and 78.6% and 72.5%, respectively, in cohort B. ORR was similar by histology (squamous, 72.0%; nonsquamous, 74.1%). Grade ≥3 pneumonitis occurred in 16 pts (7.5%) overall; 9 pts (8.0%) in cohort A and 7 (6.9%) in cohort B. Treatment-related grade ≥3 AEs occurred in 64.3% and 51.0% of pts in cohort A and B, respectively. Conclusions: With the accrual of additional responses after &gt;2 y of follow-up, pembro plus cCRT continues to demonstrate robust and durable responses, regardless of PD-L1 TPS and tumor histology, promising survival outcome and manageable safety in pts with previously untreated, locally advanced stage III NSCLC. Clinical trial information: NCT03631784. [Table: see text]
Plasma cell-free DNA integrative analysis for early detection of hepatocellular carcinoma.
Authors: Peiyao Nie, Fang Lv, Shuying He, Tiancheng Han, Shunli Yang, Li Suxing, Dan Liu, Ying Yang, Yulong LI, Yu S. Huang, Yuanyuan Hong, Weizhi Chen, Jianing Yu, Hai Dong Tan
Journal: Journal of Clinical Oncology (2022)

e16173 Background: Cell-free DNA (cfDNA) methylation, fragmentation patterns, chromosome instability, and chromatin accessiblity have been previously shown to be valid plasma biomarkers for non-invasive cancer detection. However, conventional whole-genome bisulfite sequencing (WGBS) is unable to simultaneously profile all these biomarkers due to bisulfite-induced DNA damages. Here we developed a machine learning approach to comprehensively integrate multiple types of cancer genomic markers from enzyme-conversion-based low-pass whole-methylome sequencing (WMS) of plasma cfDNA to non-invasively detect hepatocellular carcinoma. Methods: Plasma cfDNA sampels from 127 cancer patients and 568 healthy individuals were collected and were split into the discovery and independent testing cohort. The discovery cohort includes 90 cancer patients and 398 healthy individuals and the independent testing cohort includes 37 cancer patients and 170 healthy individuals. Whole methylome sequencing (WMS) libraries were generated from enzymatically converted cfDNA and were subsequently paired-end sequenced at ̃2X coverage. The genome-wide methylation density, fragmentation fingerprints, chromosome instability, and chromatin accessibility were extracted from the WMS data and individually modelled via machine learning methods such as SVM, LR, GBDT, random forest. The final predictive model is an ensemble model integrating all uni-modal models. All models were trained and fitted on the discovery cohort. Results: Data of different modalities provide complementary information in separating the cancer patients from the healthy individuals. Unsupervised clustering of the individuals showed clear separation between cancer patients and healthy individuals. The final predictive model achieved AUC =0.979 in the discovery cohort and AUC =0.98 in the independent testing cohort. Under a specificity of 96.23%(CI: 86% - 87%), sensitivity was 86% (CI: 85% - 88%) in the independent testing cohort. Separating the cancer patients into different stages, we found that the detection power is usuaul lower for early-stage cancer patients. Conclusions: These results demonstrate the first proof of principle on the feasibility of integrating multiple genomic cancer markers to non-invasively detect hepatocellular carcinoma from WMS plasma cell-free DNA. A large prospective cohort study is planned to further validate its clinical performance.
Combination therapy using microwave ablation and d-mannose-chelated iron oxide nanoparticles inhibits hepatocellular carcinoma progression
Authors: Rui Cui, Luo Wang, Dongyun Zhang, Kun Zhang, Jianping Dou, Linan Dong, Yixuan Zhang, Jiapeng Wu, Longfei Tan, Jie Yu, Ping Liang
Journal: Acta Pharmaceutica Sinica B (2022)

Despite being a common therapy for hepatocellular carcinoma (HCC), insufficient thermal ablation can leave behind tumor residues that can cause recurrence. This is believed to augment M2 inflammatory macrophages that usually play a pro-tumorigenic role. To address this problem, we designed d-mannose-chelated iron oxide nanoparticles (man-IONPs) to polarize M2-like macrophages into the antitumor M1 phenotype. In vitro and in vivo experiments demonstrated that man-IONPs specifically targeted M2-like macrophages and accumulated in peri-ablation zones after macrophage infiltration was augmented under insufficient microwave ablation (MWA). The nanoparticles simultaneously induced polarization of pro-tumorigenic M2 macrophages into antitumor M1 phenotypes, enabling the transformation of the immunosuppressive microenvironment into an immunoactivating one. Post-MWA macrophage polarization exerted robust inhibitory effects on HCC progression in a well-established orthotopic liver cancer mouse model. Thus, combining thermal ablation with man-IONPs can salvage residual tumors after insufficient MWA. These results have strong potential for clinical translation.
IMMU-19. Outcomes of Pediatric Patients with High-Risk CNS Tumors Treated with Multi-tumor associated antigen specific T cell (TAA-T) therapy: the ReMIND trial
Authors: Eugene Hwang, Fernanda Fortiz, Russell Cruz, Ashley Geiger, Melanie Grant, Haili Lang, Abeer Shibli, Sianna Burnett, Chris Lazarski, Jay Tanna, Chase McCann, Fahmida Hoq, Patrick Hanley, Lindsay Kilburn, Brian Rood, Roger Packer, Catherine Bollard
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: The ReMIND trial hypothesizes that autologous T-cells specific for three tumor-associated antigens (TAA) -WT1, PRAME, and survivin- will be safe and elicit anti-tumor immunity in pediatric patients with CNS cancer. METHODS: Patients (n=25) received autologous TAA-T for newly-diagnosed DIPG (Stratum A, up to 4x107/m2) or recurrent CNS malignancies (Stratum B, up to 8x107/m2) in this dose-escalation study (NCT03652545) and were monitored for toxicity and response. RESULTS: Autologous TAAT products were successfully manufactured from 28 patients. Using IFN-γ ELISPOT assay, 10/11 evaluable products had specificity for 1-3 TAAs. 25 patients received TAA-T (6 in Stratum A and 19 in Stratum B) and completed the 45-day safety monitoring period. Twenty-four (96%) had no dose limiting toxicities (DLT), but 1 (4%) patient with DIPG experienced a DLT related to potential immune-mediated pseudoprogression. Median overall survival for patients with DIPG (Stratum A) was 14 months (range, 6-32 months). Median progression-free survival (PFS) for Stratum B patients was 8 months (range, 2-26+ months), which exceeded their preceding median duration of disease stability of 2 months (range, 1-5 months). Plasma cytokine profiles demonstrated infusion-related immune cytokine responses. CONCLUSIONS: In summary, TAAT had a favorable toxicity profile (4%) especially compared to CAR-T therapy and may elicit anti-tumor immune responses that contribute to prolonged survival. Immunobiology studies and response assessments are ongoing for both strata. Based on these encouraging preliminary results, we have added a stratum that includes prescribed lymphodepletion pre TAA-T administration at a cell dose of 8x107/m2. Further, we plan to add an additional stratum to allow direct administration of TAA-T into the CNS via an Ommaya reservoir.
High-risk disease in newly diagnosed multiple myeloma: beyond the R-ISS and IMWG definitions
Authors: Patrick Hagen, Jiwang Zhang, Kevin Barton
Journal: Blood Cancer Journal (2022)

Abstract Multiple myeloma (MM) is an acquired malignant plasma cell disorder that develops late in life. Although progression free and overall survival has improved across all age, race, and ethnic groups, a subset of patients have suboptimal outcomes and are labeled as having high risk disease. A uniform approach to risk in NDMM remains elusive despite several validated risk stratification systems in clinical use. While we attempt to capture risk at diagnosis, the reality is that many important prognostic characteristics remain ill-defined as some patients relapse early who were defined as low risk based on their genomic profile at diagnosis. It is critical to establish a definition of high risk disease in order to move towards risk-adapted treatment approaches. Defining risk at diagnosis is important to both effectively design future clinical trials and guide which clinical data is needed in routine practice. The goal of this review paper is to summarize and compare the various established risk stratification systems, go beyond the R-ISS and international myeloma working group risk stratifications to evaluate specific molecular and cytogenetic abnormalities and how they impact prognosis independently. In addition, we explore the wealth of new genomic information from recent whole genome/exome sequencing as well as gene expression data and review known clinical factors affecting outcome such as disease burden and early relapse as well as patient related factors such as race. Finally, we provide an outlook on developing a new high risk model system and how we might make sense of co-occurrences, oncogenic dependencies, and mutually exclusive mutations.
Identification and Treatment of Opioid-Associated Out-of-Hospital Cardiac Arrest in Emergency Medical Service Protocols
Authors: David G. Dillon, Gustavo D. Porto, Vidya Eswaran, Courtney Shay, Juan Carlos C. Montoy
Journal: JAMA Network Open (2022)

This cross-sectional study reviews emergency medical services (EMS) treatment protocols for adults presenting with cardiac arrest or overdose to evaluate whether current protocols include the consideration of opioid overdose for patients with possible out-of-hospital cardiac arrest.